The goal of this project is to investigate the role of IKB kinase beta (IKK), a central coordinator of innate immunity and inflammation through activation of NF-?B, in linking obesity to adipose tissue inflammation and adipogenesis. Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The transcriptional factor NF-?B is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKK is the predominant catalytic subunit of the IKK complex that is required for canonical activation of NF-?B by inflammatory mediators. Given the defined role of IKK in regulating NF-?B-mediated inflammation in several cell types, it is unclear whether IKK contributes to obesity-induced inflammation in adipocytes. In the proposed studies, we will define the role of adipocyte-derived IKK in high fat (HF) diet-induced obesity, adipose inflammation and insulin resistance. In preliminary studies during Phase I support of this project, we also defined the role of smooth muscle cell (SMC) IKK in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKK in SMCs, we used SM22-Cre transgenic male mice carrying floxed IKK alleles that were mated to female LDLR-/- mice carrying floxed IKK alleles. During the course of these studies, we made the novel finding that deficiency of IKK in SMCs rendered mice resistant to the development of diet-induced obesity. Preliminary results demonstrate that SM22 is expressed in primary adipose stromal/vascular (SV) cells, consistent with recent reports that SM22-Cre is active in mesenchymal stem cells (MSCs) that give rise to adipose tissue. Notably, SV cells from SMC IKK-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKK in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKK promotes adipocyte differentiation, adipocyte inflammation, and insulin resistance. In the proposed studies, we will define mechanisms for IKK-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKK deficiency on the development of obesity, adipose inflammation, and insulin resistance in response to a HF diet. The proposed studies will elucidate new aspects of adipocyte biology and metabolic control and may lead to novel therapeutic targets for obesity and diabetes.